Ester pro-drugs of [3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for lowering intraocular pressure

ABSTRACT

The present invention relates to method of lowering intraocular pressure in a subject in need of such treatment, which comprises administering a therapeutically effective amount of a composition comprising a ester pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of enantiomers thereof, of tautomers thereof, pharmaceutical compositions containing them and their use as pharmaceuticals.

RELATED APPLICATIONS

This application is a divisional of U.S. Non-Provisional patentapplication Ser. No. 13/233,844 filed Sep. 15, 2011, which claims thebenefit of U.S. Provisional Patent Application No. 61/383,370 filed onSep. 16, 2010, all of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method of lowering intraocularpressure in a subject in need of such treatment, which comprisesadministering a therapeutically effective amount of a compositioncomprising ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanolor of itsenantiomers.

2. Summary of the Related Art

Three alpha-1 and three alpha-2 adrenergic receptors have beencharacterized by molecular and pharmacological methods. Activation ofthese alpha receptors evokes physiological responses with usefultherapeutic applications.

Compound, 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole, genericallyknown as, medetomidine is an alpha 2 adrenergic agonist, for use in thesedation of animals. The hydrochloride salt of the (S) enantiomer ofmedetomidine, generically known as dexmedetomidine, (S)4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole, is also indicated for useas a sedative or analgesic in cats and dogs.

The metabolite of dexmedetomidine is (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol together with itsracemic mixture, compound[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, are described inthe literature in Journal of Chromatography, (1997), 762(1+2), 281-291by Hui, Y.-H et al.[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol is described in“Synthesis of detomidine and medetomidine metabolites:1,2,3-trisubstituted arenes with 4′(5′)-imidazolylmethyl groups” inJournal of Heterocyclic Chemistry (1993), 30(6), (1645-1651) by Stoilovet al.

Kavanagh, et al. describe[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol in “Synthesis ofPossible Metabolites of Medetomidine{1-(2,3-dimethylphenyl)-1-[imidazol-4(5)-yl]ethane” in Journal ofChemical Research, Synopses (1993), (4), 152-3.

[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol] is described bySalonen, et al. in “Biotransformation of Medetomidine in the Rat” inXenobiotica (1990), 20(5), 471-80.

PCT Int. Appl. WO 2010093930 A1 discloses[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and its (S) and(R) enantiomers

SUMMARY OF THE INVENTION

Three alpha 1 and three alpha 2 adrenergic receptors have beencharacterized by molecular and pharmacological methods. Activation ofthese alpha 2 receptors evokes physiological responses and has usefultherapeutic actions.

The adrenergic Alpha-2 agonists play a key role in modulating aqueoushumor formation and facilitating aqueous outflow; as a result thesecompounds lower intraocular pressure (IOP) in glaucomatous patients. Twodrugs are currently prescribed for glaucoma patients, Apraclonidine(Iopidine® available from Alcon Pharmaceuticals) and Brimonidine(Alphagan P® available from Allergan, Inc.). While these drugs areeffective at lowering elevated intraocular pressure, Alphagan P® is theonly alpha-2 adrenergic drug approved for chronic treatment of glaucoma,but it loses effect during the day and must be used 2-3 times a day,while Iopidine® is only approved for short term IOP control. Consideringthe aged glaucoma patient population, a 3 times per day dosing frequencyis far from optimal and may result in poor patient compliance.

The present invention relates to a method of lowering intraocularpressure in a subject in need of such treatment, which comprisesadministering a therapeutically effective amount of a compositioncomprising ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol. Upon hydrolyticand/or enzymatic cleavage of the ester functionality the parentcompound, [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, isreleased to act as a selective modulator of the alpha 2 adrenergicreceptors.

In another aspect, the present invention relates to a method of loweringintraocular pressure in a subject in need of such treatment, whichcomprises administering a therapeutically effective amount of acomposition comprising ester pro-drugs of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, orpharmaceutical compositions containing them. Upon hydrolytic and/orenzymatic cleavage of the ester functionality the parent compound,active metabolite, (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is released toact as a selective modulator of the alpha 2 adrenergic receptors.

In another aspect the present invention provides relates to a method oflowering intraocular pressure in a subject in need of such treatment,which comprises administering a therapeutically effective amount of acomposition comprising ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, orpharmaceutical compositions containing them. Upon hydrolytic and/orenzymatic cleavage of the ester functionality the parent compound (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is released toact as a selective modulator of the alpha 2 adrenergic receptors.

The ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol are useful forthe treatment or prevention of mammals, including humans, in a range ofconditions and diseases that are alleviated by alpha 2A, 2B, 2Cactivation, including but not limited to treating or preventingglaucoma, elevated intraocular pressure, ischemic neuropathies, opticneuropathy, pain, visceral pain, corneal pain, headache pain, migraine,cancer pain, back pain, irritable bowel syndrome pain, muscle pain andpain associated with diabetic neuropathy, the treatment of diabeticretinopathy, other retinal degenerative conditions, stroke, cognitivedeficits, neuropsychiatric conditions, drug dependence and addiction,withdrawal of symptoms, obsessive-compulsive disorders, obesity, insulinresistance, stress-related conditions, diarrhea, diuresis, nasalcongestion, spasticity, attention deficit disorder, psychoses, anxiety,depression, autoimmune disease, Crohn's disease, gastritis, Alzheimer's,and Parkinson's ALS other neurodegenerative diseases, dermatologicalconditions, skin erythema (redness) and inflammation, acne, age relatedmacular degeneration, wet macular degeneration, dry maculardegeneration, geographic atrophy, diabetic macular edema, tumors, woundhealing, inflammation and retinal vein occlusion, enhancing vision inpatients with vision loss from conditions including glaucoma, retinitispigmentosa and neuritis secondary to multiple sclerosis, rosacea(dilation of the blood vessels just under the skin), sunburn, chronicsun damage, discreet erythemas, psoriasis, acne rosacea,menopause-associated hot flashes, hot flashes resulting fromorchiectomyatopic dermatitis, photoaging, seborrheic dermatitis,allergic dermatitis, redness of the skin, telangiectasia (dilations ofpreviously existing small blood vessels) of the face, rhinophymia(hypertrophy of the nose with follicular dilation), red bulbous nose,acne-like skin eruptions (may ooze or crust), burning or stingingsensation of the face, irritated and bloodshot and watery eyes, erythemaof the skin, cutenous hyperactivity with dilation of blood vessels ofthe skin, Lyell's syndrome, Stevens-Johnson syndrome, erythemamultiforme minor, erythema multiforme major and other inflammatory skindiseases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows compound Isobutyric acid3-[(S)-1-(1-isobutyryl-1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester(Compound 1) has equal or comparable efficacy to Alphagan P® and haslonger intraocular pressure duration than Alphagan P®.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of lowering intraocularpressure in a subject in need of such treatment, which comprises,consists essentially of, or consists of administering a therapeuticallyeffective amount of a composition comprising ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, ester pro-drugsof (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or esterpro-drugs of (R) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanolas alpha-2 agonists with therapeutic utility.

In a preferred embodiment the present invention relates to a method oflowering intraocular pressure in a subject in need of such treatment,which comprises, consists essentially of, or consists of administering atherapeutically effective amount of a composition comprising esterspro-drugs of (S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanolas alpha-2 agonists with therapeutic utility. Upon hydrolytic orenzymatic cleavage of the ester functionality the parent compound,active metabolite,(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is releasedto act as a selective modulator of the alpha 2 adrenergic receptors.

In one aspect of the invention, there is provided a method of loweringintraocular pressure in a patient in need thereof which comprises,consists essentially of or consists of administering a therapeuticallyeffective amount of a pharmaceutical composition comprising, consistingessentially of or consisting of a therapeutically effective amount ofester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or theenantiomers thereof, or the tautomers thereof, or pharmaceuticallyacceptable salts thereof.

In another aspect of the invention, there is provided a method oflowering intraocular pressure in a patient in need thereof whichcomprises, consists essentially of or consists of administering atherapeutically effective amount of a pharmaceutical compositioncomprising, consisting essentially of or consisting of a therapeuticallyeffective amount of ester pro-drugs of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the tautomersthereof, or pharmaceutically acceptable salts thereof.

In another aspect of the invention, there is provided a method oflowering intraocular pressure in a patient in need thereof whichcomprises, consists essentially of or consists of administering atherapeutically effective amount of a pharmaceutical compositioncomprising, consisting essentially of or consisting of a therapeuticallyeffective amount of ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the tautomersthereof, or pharmaceutically acceptable salts thereof.

In another aspect of the invention, there is provided a method oflowering intraocular pressure of a patient in need thereof whichcomprises, consists essentially of or consists of administering atherapeutically effective amount of a pharmaceutical compositioncomprising, consisting essentially of or consisting of a therapeuticallyeffective amount of ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or theenantiomers thereof, or the tautomers thereof, or pharmaceuticallyacceptable salts thereof, to the affected eye of said patient, as asingle dose, wherein the affected eye maintains an intraocular pressureless than the baseline intraocular pressure for at least eight (8) hoursand preferably at least ten (10) hours and more preferably at leasttwelve (12) hours, from the time of administration.

The term “baseline”, as used herein, refers to the intraocular pressuremeasurement taken for the untreated eye.

The term “subject”, as used herein, refers to a human patient.

In a still further aspect of the invention, there is provided a methodof lowering intraocular pressure of a patient in need thereof whichcomprises administering a therapeutically effective amount of acomposition comprising ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or theenantiomers thereof, or the tautomers thereof, or pharmaceuticallyacceptable salts thereof, to the affected eye of said patient, once ortwice daily, preferably once daily, wherein the affected eye maintainsan intraocular pressure less than the baseline intraocular pressure,throughout the day.

In another aspect of the invention, there is provided a method oflowering intraocular pressure of a patient in need thereof whichcomprises, consists essentially of or consists of administering atherapeutically effective amount of a pharmaceutical compositioncomprising, consisting essentially of or consisting of a therapeuticallyeffective amount of ester pro-drugs of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the tautomersthereof, or pharmaceutically acceptable salts thereof, to the affectedeye of said patient, as a single dose, wherein the affected eyemaintains an intraocular pressure less than the baseline intraocularpressure for at least eight (8) hours and preferably at least ten (10)hours and more preferably at least twelve (12) hours, from the time ofadministration.

In a still further aspect of the invention, there is provided a methodof lowering intraocular pressure of a patient in need thereof whichcomprises administering a therapeutically effective amount of acomposition comprising ester pro-drugs of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the tautomersthereof, or pharmaceutically acceptable salts thereof, to the affectedeye of said patient, once or twice daily, preferably once daily, whereinthe affected eye maintains an intraocular pressure less than thebaseline intraocular pressure, throughout the day.

In another aspect of the invention, there is provided a method oflowering intraocular pressure of a patient in need thereof whichcomprises, consists essentially of or consists of administering atherapeutically effective amount of a pharmaceutical compositioncomprising, consisting essentially of or consisting of a therapeuticallyeffective amount of ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the tautomersthereof, or pharmaceutically acceptable salts thereof, to the affectedeye of said patient, as a single dose, wherein the affected eyemaintains an intraocular pressure less than the baseline intraocularpressure for at least eight (8) hours and preferably at least ten (10)hours and more preferably at least twelve (12) hours, from the time ofadministration.

In a still further aspect of the invention, there is provided a methodof lowering intraocular pressure of a patient in need thereof whichcomprises administering a therapeutically effective amount of acomposition comprising ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the tautomersthereof, or pharmaceutically acceptable salts thereof, to the affectedeye of said patient, once or twice daily, preferably once daily, whereinthe affected eye maintains an intraocular pressure less than thebaseline intraocular pressure, throughout the day.

“Prodrugs” are frequently referred to by the term “metabolicallycleavable derivatives” which refers to compound forms which are rapidlytransformed in vivo to the parent compound according to the invention,for example, by hydrolysis in blood. Thus, prodrugs are compoundsbearing groups which are removed by biotransformation prior toexhibiting their pharmacological action. Such groups include moietieswhich are readily cleaved in vivo from the compound bearing it, whichcompound after cleavage remains or becomes pharmacologically active.Such metabolically cleavable groups form a class well known topractitioners of the art. They include, but are not limited to suchgroups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like),unsubstituted and substituted carbocyclic aroyl (such as benzoyl,substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such asethoxycarbonyl), trialklysilyl (such as trimethyl- and triethylsilyl),monoesters formed with dicarboxylic acids (such as succinyl), phosphate,sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compoundsbearing the metabolically cleavable groups have the advantage that theymay exhibit improved bioavailability as a result of enhanced solubilityand/or rate of absorption conferred upon the parent compound by virtueof the presence of the metabolically cleavable group. (T. Higuchi and V.Stella, “Pro-drugs as Novel Delivery System”, Vol. 14 of the A.C.S.Symposium Series; “Bioreversible Carriers in Drug Design”, ed. Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987).

In one aspect, the invention therefore relates to a method of loweringintraocular pressure in a subject in need of such treatment, whichcomprises administering a therapeutically effective amount of acomposition comprising a compound having Formula I, its individualenantiomers, its individual diastereoisomers, its individual hydrates,its individual solvates, its individual crystal forms, its individualisomers, its individual tautomers or a pharmaceutically acceptable saltthereof,

whereinR¹ is H or C₁₋₃ alkyl;R² is H or C₁₋₃ alkyl;R³ is H, C₁₋₁₀ alkyl, heterocycle or aryl; andR is C₁₋₁₀ alkyl, heterocycle or aryl.

In a preferred aspect, the invention therefore relates to a method oflowering intraocular pressure in a subject in need of such treatment,which comprises administering a therapeutically effective amount of acomposition comprising a compound having Formula II, its individualdiastereoisomers, its individual hydrates, its individual solvates, itsindividual crystal forms, its individual isomers, its individualtautomers or a pharmaceutically acceptable salt thereof,

whereinR¹ is H or C₁₋₃ alkyl;R² is H or C₁₋₃ alkyl;R³ is H, C₁₋₁₀ alkyl, heterocycle or aryl; andR is C₁₋₁₀ alkyl, heterocycle or aryl.

In another aspect, the invention therefore relates to a method oflowering intraocular pressure in a subject in need of such treatment,which comprises administering a therapeutically effective amount of acomposition comprising a compound having Formula III, its individualdiastereoisomers, its individual hydrates, its individual solvates, itsindividual crystal forms, its individual isomers, its individualtautomers or a pharmaceutically acceptable salt thereof,

whereinR¹ is H or C₁₋₃ alkyl;R² is H or C₁₋₃ alkyl;R³ is H, C₁₋₁₀ alkyl, heterocycle or aryl; andR is C₁₋₁₀ alkyl, heterocycle or aryl.

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds of the invention and are intended toapply uniformly throughout the specification and claims unless expresslystated otherwise.

The term “alkyl” as used herein, is defined as including a saturatedmonovalent alkane moiety having straight or branched alkane moieties orcombinations thereof and containing 1-10 carbon atoms, preferably 1-8carbon atoms and more preferably 1-4 carbon atoms. Alkyl moieties canoptionally be substituted by, but not limited to, amino groups, arylgroups, halogens. One methylene (—CH₂—) group can be replaced bycarbonyl, —NH—, carboxyl, amide, sulfur or by oxygen. Examples include,but are not limited to, methyl, ethyl, propyl, butyl, sec-butyl, pentyl,iso-pentyl, neo-pentyl, hexyl, iso-hexyl, 3-methyl-butyl,2-amino-N-isobutyl acetamide, iso-butyl, tert-butyl, iso-propyl,ethylphenyl, methylphenyl,2-amino-3-methyl-butanamide-N-2-methyl-1-propyl,1-amino-2-methyl-prop-1-yl.

The term “heterocycle” as used herein is defined as an aromatic or nonaromatic 5 to 10 membered monocyclic or bicyclic ring containing atleast one heteroatom selected from O or N or S or combinations thereof,interrupting the carbocyclic ring structure. Heterocycles can optionallybe substituted by, but not limited to, C₁₋₆ alkyl, amino, halogen,—O(C₁₋₆ alkyl), —OC(O)(C₁₋₆ alkyl), —C(O)O(C₁₋₆ alkyl), —NHC(O)(C₁₋₆alkyl), —C(O)NH(C₁₋₆ alkyl), —S(C₁₋₆ alkyl) groups. Examples include,but are not limited to, furyl, pyrryl, pyridyl, pyrimidyl, thienyl,isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl,isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,isothiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, isooxazolyl,quinazolinyl, pyridazinyl, cinnolinyl, phthalazinyl, quinoxalinyl,xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, pyrrolidinyl, piperidinyl and piperazinyl.

The term “aryl” as used herein, is defined as including an organicmoiety derived from an aromatic hydrocarbon consisting of a monocyclicor bicyclic ring containing 6-10 carbon atoms by removal of one hydrogenatom, such as phenyl or naphtyl. Aryl groups can optionally besubstituted by, but not limited to, C₁₋₆ alkyl, amino, halogen, —O(C₁₋₆alkyl), —OC(O)(C₁₋₆ alkyl), —C(O)O(C₁₋₆ alkyl), —NHC(O)(C₁₋₆ alkyl),—C(O)NH(C₁₋₆ alkyl), —S(C₁₋₆ alkyl) groups. Examples include, but arenot limited to, phenyl, naphtyl.

The term “H” as used herein refers to a hydrogen atom.

The term “O” as used herein refers to an oxygen atom.

The term “S” as used herein refers to a sulfur atom.

The term “N” as used herein refers to a nitrogen atom.

The term “amino” as used herein refers to a group of formula —NH₂.

The term “amide” as used herein refers to a group of formula —C(O)NH— or—NHC(O)—.

The term “halogen”, as used herein refers to an atom of chlorine,bromine, iodine or fluorine.

The term “carbonyl” as used herein refers to a group of formula —C═O.

The term “carboxyl”, as used herein refers to a group of formula —C(O)O—or —OC(O)—.

Generally R¹ is H or C₁₋₃ alkyl. Preferred R¹ is C₁₋₃ alkyl. Mostpreferred R¹ is methyl.

Generally R² is H or C₁₋₃ alkyl. Preferred R² is C₁₋₃ alkyl. Mostpreferred R² is methyl.

Generally R³ is H, C₁₋₁₀ alkyl, heterocycle or aryl. Preferred R³ is H,phenyl or C₁₋₁₀ alkyl. Most preferred R³ is H.

Generally R is C₁₋₁₀ alkyl, heterocycle or aryl. Preferred R is methyl,iso-butyl, tert-butyl, iso-propyl, ethylphenyl, phenyl,2-amino-1-phenylethyl,2-(2-amino-3-methyl-butyrylamino)-2-methyl-prop-1-yl,1-amino-2-methyl-prop-1-yl, 2-(2-amino-acetylamino)-2-methyl-prop-1-yl.Most preferred R groups are tert-butyl, iso-propyl.

As used herein, “tautomer” refers to the migration of protons betweenadjacent single and double bonds. The tautomerization process isreversible. Compounds described herein can undergo any possibletautomerization that is within the physical characteristics of thecompound. The following is a tautomerization example that can occur incompounds described herein:

Compounds of the invention are:

-   iso-Butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl    ester;-   2,2-Dimethyl-propionic acid    3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;-   Acetic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;-   Benzoic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl    ester;-   3-Methyl-butyric acid    3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;-   3-Phenyl-propionic acid    3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;-   2-Amino-3-methyl-butyric acid    3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;-   2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid    3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;-   2-(2-Amino-acetylamino)-3-methyl-butyric acid    3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;-   2-Amino-3-phenyl-propionic acid    3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester.

Intermediates of the invention are:

-   iso-Butyric acid    3-[(S)-1-(1-iso-butyryl-1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl    ester;-   2,2-Dimethyl-propionic acid    3-{(S)-1-[1-(2,2-dimethyl-propionyl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzyl    ester;-   Acetic acid    3-[(S)-1-(1-acetyl-1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;-   Benzoic acid    3-[(S)-1-(1-benzoyl-1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;-   3-Methyl-butyric acid    2-methyl-3-{(S)-1-[1-(3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-benzyl    ester;-   Phenyl-propionic acid    2-methyl-3-{(S)-1-[1-(3-phenyl-propionyl)-1H-imidazol-4-yl]-ethyl}-benzyl    ester;-   2-tert-Butoxycarbonylamino-3-methyl-butyric acid    3-{(S)-1-[1-(2-tert-butoxy    carbonylamino-3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzyl    ester;-   2-tert-Butoxycarbonylamino-3-methyl-butyric acid    3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;-   2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyric    acid    3-{(S)-1-[1-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzyl    ester;-   2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyric    acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;-   2-(2-tert-Butoxycarbonylamino-acetylamino)-3-methyl-butyric acid    3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;-   2-tert-Butoxycarbonylamino-3-phenyl-propionic acid    3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester.

Some compounds of Formula I, Formula II and Formula III and some oftheir intermediates have at least one stereogenic center in theirstructure. This stereogenic center may be present in an (R) or (S)configuration, said (R) and (S) notation is used in correspondence withthe rules described in Pure Appli. Chem. (1976), 45, 11-13.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

Compounds of Formula I, Formula II or Formula III and their salts can bein the form of a solvate, which is included within the scope of thepresent invention. Such solvates include for example hydrates,alcoholates and the like.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I, Formula II or Formula III areable to form.

The acid addition salt form of a compound of Formula I, Formula II orFormula III that occurs in its free form as a base can be obtained bytreating the free base with an appropriate acid such as an inorganicacid, for example but not limited to, hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, nitric acid and the like; or anorganic acid such as for example but not limited to, as citric acid,acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid,alginic acid, polyglutamic acid, naphthalene-sulfonic acid,napthalenedisulfonic, and polygalacturonic acid as well as base additionsalts such as those formed with alkali- and alkaline earth metals suchas sodium, potassium and calcium and the like (Handbook ofPharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds),Verlag Helvetica Chemica Acta-Zürich, 2002, 329-345).

The compounds can also be administered as pharmaceutically acceptablequaternary salts known by those skilled in the art, which specificallyinclude, but not limiting to the quaternary ammonium salt of the formula—NY⁺Z⁻, wherein Y is hydrogen, alkyl, or benzyl, and Z is a counterion,including but not limited to, chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as fumarate, benzoate, succinate, acetate, glycolate, maleate,malate, fumarate, citrate, tartrate, ascorbate, benzoate, cinnamoate,mandeloate, benzyloate, and diphenylacetate).

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include but are notlimited to, glucose, lactose, gum acacia, gelatin, mannitol, starchpaste, magnesium trisilicate, talc, corn starch, keratin, colloidalsilica, potato starch, urea, medium chain length triglycerides,dextrans, and other carriers suitable for use in manufacturingpreparations, in solid, semisolid, or liquid form. In additionauxiliary, stabilizing, thickening and coloring agents and perfumes maybe used. Invention compounds are included in the pharmaceuticalcomposition in an amount sufficient to produce the desired effect uponthe process or disease condition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. In some cases, formulations for oral use may be in theform of hard gelatin capsules wherein the invention compounds are mixedwith an inert solid diluent, for example, calcium carbonate, calciumphosphate or kaolin. They may also be in the form of soft gelatincapsules wherein the invention compounds are mixed with water or an oilmedium, for example, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The present invention concerns also the use of a compound of Formula I,Formula II or Formula III, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the therapeuticapplication. The present invention concerns also the a method formanufacturing a medicament intended for therapeutic application whereina compound having general Formula I, Formula II or Formula III, or apharmaceutically active derivative or salt thereof is used.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner. The patient will beadministered the compound orally in any acceptable form, such as atablet, liquid, capsule, powder and the like, or other routes may bedesirable or necessary, particularly if the patient suffers from nausea.Such other routes may include, without exception, transdermal,parenteral, subcutaneous, intranasal, via an implant stent, intrathecal,intravitreal, topical to the eye, back to the eye, intramuscular,intravenous, and intrarectal modes of delivery. The actual amount of thecompound to be administered in any given case will be determined by aphysician taking into account the relevant circumstances, such as theseverity of the condition, the age and weight of the patient, thepatient's general physical condition, the cause of the condition, andthe route of administration. Additionally, the formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and theirpharmaceutically-acceptable salts may be administered through differentroutes, including but not limited to topical eye drops, directinjection, application at the back of the eye or formulations that mayfurther enhance the long duration of actions such as a slow releasingpellet, suspension, gel, or sustained delivery devices such as anysuitable drug delivery system (DDS) known in the art. While topicaladministration is preferred, this compound may also be used in anintraocular implant as described in U.S. U.S. Pat. No. 7,931,909 whichis hereby incorporated by reference. Such biocompatible intraocularimplants include ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and a polymerassociated with ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol to facilitaterelease thereof into an eye for an extended period of time. Ophthalmicformulations of drug products are well known in the art and describedin, for example, U.S. Patent Application Publication No. 20050059583;No. 20050277584; U.S. Pat. No. 7,297,679; and No. 20070015691; and U.S.Pat. Nos. 5,474,979 and 6,582,718, the disclosures of all which areincorporated herein by reference. The ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol may be formulatedwith efficacy enhancing components as disclosed in U.S. Pat. No.7,491,383 B2, which is hereby incorporated by reference in its entirety.

In one method of the invention, said intraocular pressure is lowered forat least eight (8) hours subsequent to administration.

In a preferred method of the invention, said intraocular pressure islowered for at least ten (10) hours subsequent to administration.

In a more preferred method of the invention, said intraocular pressureis lowered for at least twelve (12) hours subsequent to administration.

In the method according to the present invention, the composition thatis used, as a single dose, to lower intraocular pressure for at leasteight (8) hours and preferably at least ten (10) hours and morepreferably for at least twelve (12) hours, may comprise from 0.0005 to 5percent, preferably from 0.005 to 2 percent, more preferably from 0.05to 2 percent by weight of ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, in apharmaceutically-acceptable vehicle.

In another aspect of the invention, the method according to the presentinvention, the composition that is used, as a single dose, to lowerintraocular pressure for at least eight (8) hours and preferably atleast ten (10) hours and more preferably for at least twelve (12) hours,may comprise from 0.01 to 5 percent, preferably from 0.01 to 2 percent,more preferably from 0.05 to 2 percent by weight of ester pro-drugs of(S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol in apharmaceutically-acceptable vehicle. In another aspect of the invention,the method according to the present invention, the composition that isused, as a single dose, to lower intraocular pressure for at least eight(8) hours and preferably at least ten (10) hours and more preferably forat least twelve (12) hours, may comprise from 0.01 to 5 percent,preferably from 0.01 to 2 percent, more preferably from 0.05 to 2percent by weight of ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol in apharmaceutically-acceptable vehicle.

In forming compositions for topical administration, the pharmaceuticalcompositions are preferably formulated as a solution in water at a pH of5.5 to 8.0, e.g. about 6.9. Said composition is preferably formulated asan eye drop suitable for topical administration. While the preciseregime is left to the discretion of the clinician, it is recommendedthat the solution be topically applied by placing one drop in each eyeone or two times, preferably once a day. Other ingredients which may bedesirable to use in the ophthalmic preparations used in the method ofthe present invention include preservatives, co-solvents and viscositybuilding agents; bodium chloride, potassium chloride, calcium chloridedihydrate, magnesium chloride hexahydrate, boric acid and sodium boratedecahydrate (as buffering agents) and purified water (Clinical OcularPharmacology By Jimmy D. Bartlett, Siret D. Jaanus, 2008, p 266).

Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: stabilized oxychloro complex(sold under the trademark Purite™), stabilized chlorine dioxide,benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M,or other agents known to those skilled in the art (Review ofOphthalmology, June 2001, Robert Noecker, MD). A common side-effect ofthese preservatives is burning.

Typically, for the compositions utilized in the method of the presentinvention, the effective concentration of the preservative will rangefrom 0.001% to 1%, preferably from 0.01% to 0.5%, by weight. Inparticular stabilized oxychloro complex (Purite®) will range from 0.001to 0.01%, by weight.

The solubility of the components of the present compositions may beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such cosolvents include polysorbate 20, 60, and 80,Pluronic® F-68, F-84 and P-103, cyclodextrin, Solutol, or other agentsknown to those skilled in the art. Typically such co-solvents areemployed at a level of from 0.01% to 2% by weight.

Viscosity increased above that of simple aqueous solutions may bedesirable to increase ocular absorption of the active compound, todecrease variability in dispensing the formulation, to decrease physicalseparation of components of a suspension or emulsion of the formulationand/or to otherwise improve the ophthalmic formulation. Such viscositybuilding agents include as examples polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl celluloseor other agents known to those skilled in the art. Such agents aretypically employed at a level of from 0.01% to 2% by weight.

The following formulations are representative ophthalmic compositions ofthe invention for topical use when indicated for treating elevatedintraocular pressure associated with glaucoma. In one example, the freebase of ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the free baseof ester pro-drugs of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or the free baseof ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol was dissolved insterile distilled water, hydrochloric acid was added and thehydrochloric salt of the compound was formed in situ. The solution wastitrated with sodium hydroxide until the pH of the solution reached 8.0.The final concentration of ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or of esterpro-drugs of (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanolor of ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol is 1% by weight.In another example, the free base of ester pro-drugs of[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the free baseof ester pro-drugs of (S)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or the free baseof ester pro-drugs of (R)[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol was dissolved insterile distilled water with boric acid, benzalkonium chloride andglycerin.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

The present invention also concerns a process for preparing thecompounds having general Formula I, Formula II or Formula III.

The synthetic scheme set forth below, illustrates how compoundsaccording to the invention can be made. Those skilled in the art will beable to routinely modify and/or adapt the following scheme to synthesizeany compounds of the invention covered by Formula I, Formula II orFormula III.

General Scheme for Synthesizing Ester Prodrugs of(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol

In a first step(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (CAS189255-79-6) can react with the desired acyl chloride, in the presenceof N,N-dimethyl formamide (DMF), tertahydrofuran (THF), triethylamine(TEA) and 4-dimethyl aminopyridine (DMAP). After a typical work-up byextraction, the residue can be purified by medium pressure liquidchromatography (MPLC) (0% to 40% ethyl acetate in hexanes) to yield theintermediate compound as solid.

In a second step, the intermediate obtained in the first reaction, canreact with methanol (MeOH). The residue can be purified by MPLC (50%ethyl acetate in hexanes then 5% 7N ammonia/methanol/dichloromethane) toyield the desired compound as a solid.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

The IUPAC names of the compounds mentioned in the examples weregenerated with ACD version 8.

Unless specified otherwise in the examples, characterization of thecompounds is performed according to the following methods:

NMR spectra are recorded on 300 MHz Varian and acquired at roomtemperature. Chemical shifts are given in ppm referenced either tointernal TMS or to the residual solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Lancaster, however some known reaction intermediates, for whichthe CAS registry number is mentioned, were prepared in-house followingknown procedures.

Usually the compounds of the invention were purified by flash columnchromatography.

The following abbreviations are used in the examples:

DCM dichloromethaneMeOH methanolCD₃OD deuterated methanolNH₃ ammoniaNa₂SO₄ sodium sulfate

DMF N,N-dimethylformamide

MgSO₄ magnesium sulfateEtOAc ethylacetatei-PrOH iso-propanolCDCl₃ deuterated chloroformMPLC medium pressure liquid chromatographyDMF dimethylformamideTEA triethylamineTHF tertahydrofuranDMAP 4-dimethylaminopyridineRT room temperature

Boc-L-Valine N-(tert-Butoxycarbonyl)-L-valine Boc-GlycineN-(tert-Butoxycarbonyl)glycine Boc-L-PhenylalanineN-(tert-Butoxycarbonyl)-L-phenylalanine

HCl hydrochloric acidH₂O waterEDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimideNaHCO₃ sodium bicarbonate

Example 1 Intermediate 1 iso-Butyric acid3-[(S)-1-(1-isobutyryl-1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

To a solution of(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (1.34 g, 6.2mmol) in DMF (8 ml) and THF (50 ml), were added TEA (3.5 ml, 24.8 mmol),DMAP (780 mg, 6.2 mmol) and iso-butyryl chloride (2.18 g, 20.5 mmol).The resulting mixture was stirred at RT for 16 h, quenched with H₂O andextracted with ethyl acetate. The combined organic layers were washedwith brine, and dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by MPLC (0% to 40% ethyl acetate inhexanes) to yield Intermediate 1 as a solid.

¹H-NMR (CD₃OD, δ ppm): 1.15 (d, J=7.03 Hz, 6H), 1.26 (d, 6H, J=6.74 Hz),1.56 (d, J=7.03 Hz, 3H), 2.34 (s, 3H), 2.58 (hept, J=7.03 Hz, 1H), 3.34(hept, J=7.74 Hz, 1H), 4.42 (q, J=7.03 Hz, 1H), 5.15 (s, 2H), 7.07-7.10(m, 2H), 7.12-7.15 (m, 1H), 7.31 (s, 1H), 8.35 (s, 1H).

Intermediates 2-6 were prepared in a similar manner to the methoddescribed in Example 1 starting with(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol. The acylchloride used in each case and the results are tabulated below in Table1.

TABLE 1 Inter- mediate Acyl number IUPAC name chloride ¹ NMR (Solvent; δppm) 2 2,2-Dimethyl-propionic acid Pivaloyl (CD₃OD): 1.19 (s, 9H),3-{(S)-1-[1-(2,2-dimethyl- chloride 1.42 (s, 9H), 1.56 (d,propionyl)-1H-imidazol-4- J = 7.03 Hz, 3H), 2.34yl]-ethyl}-2-methyl-benzyl (s, 3H), 4.42 (q, ester J = 7.03 Hz, 1H),5.15 (s, 2H), 7.07-7.10 (m, 2H), 7.12-7.15 (m, 1H), 7.33 (s, 1H), 8.40(s, 1H). 3 Acetic acid 3-[(S)-1-(1- Acetyl (CD₃OD): 1.55 (d,acetyl-1H-imidazol-4-yl)- chloride J = 7.03 Hz, 3H), 2.05ethyl]-2-methyl-benzyl ester (s, 3H), 2.33 (s, 3H), 2.58 (s, 3H), 4.39(q, J = 7.03 Hz, 1H), 5.15 (s, 2H), 7.07-7.10 (m, 2H), 7.12-7.15 (m,1H), 7.30 (s, 1H), 8.29 (s, 1H). 4 Benzoic acid 3-[(S)-1-(1- Benzoyl(CD₃OD): 1.58 (d, benzoyl-1H-imidazol-4-yl)- chloride J = 7.03 Hz, 3H),2.43 ethyl]-2-methyl-benzyl (s, 3H), 4.46 (q, ester: J = 7.03 Hz, 1H),5.41 (s, 2H), 7.11-7.18 (m, 2H), 7.27-7.35 (m, 2H), 7.42-7.50 (m, 2H),7.50-7.63 (m, 3H), 7.65-7.71 (m, 1H), 7.79 (d, J = 7.33 Hz, 2H), 8.00(d, J = 7.33 Hz, 2H), 8/09 (s, 1H). 5 3-Methyl-butyric acid 2- Methyl-(CD₃OD): 0.91 (d, methyl-3-{(S)-1-[1-(3- butanoyl J = 6.44 Hz, 6H), 1.01methyl-butyryl)-1H- chloride (d, J = 6.44 Hz, 6H),imidazol-4-yl]-ethyl}-benzyl 1.54 (d, J = 7.03 Hz, ester 3H), 2.05(hept, J = 6.44 Hz, 1H), 2.15- 2.25 (m, 3H), 2.33 (s, 3H), 2.81 (d, J =7.03 Hz, 3H), 4.42 (q, J = 7.03 Hz, 1H), 5.14 (s, 2H), 7.07-7.19 (m,3H), 7.28 (s, 1H), 8.32 (s, 1H). 6 3-Phenyl-propionic acid 2- Phenyl-(CD₃OD): 1.52 (d, methyl-3-{(S)-1-[1-(3- propanoyl J = 7.03 Hz, 3H),2.24 phenyl-propionyl)-1H- chloride (s, 3H), 2.64 (t,imidazol-4-yl]ethyl}-benzyl J = 7.61 Hz, 2H), 2.90 ester (t, J = 7.61Hz, 2H), 3.04 (t, J = 7.61 Hz, 2H), 3.24 (t, J = 7.61 Hz, 2H), 4.34 (q,J = 7.03 Hz, 1H), 5.13 (s, 2H), 7.08- 7.248 (m, 14H), 8.25 (s, 1H).

Example 2 Compound 1 iso-Butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

Intermediate 1 was dissolved in MeOH (50 ml) and the mixture was stirredat RT for 24 h and then concentrated under reduced pressure. The residuewas purified by MPLC (50% ethyl acetate in hexanes then 5% 7NNH₃/MeOH/DCM) to yield Compound 1 as a solid.

¹H-NMR (CD₃OD; δ ppm): 1.15 (d, J=7.03 Hz, 6H), 1.54 (d, J=7.03 Hz, 3H),2.33 (s, 3H), 2.56 (hept, J=7.03 Hz, 1H), 4.42 (q, J=7.03 Hz, 1H), 5.15(s, 2H), 6.70 (s, 1H), 7.07-7.10 (m, 2H), 7.12-7.15 (m, 1H), 7.55 (s,1H).

Compounds 2-6 and of the invention were prepared according to theprocedure described in Example 2, by reacting the correspondingintermediate with methanol. The results are tabulated below in Table 2.

TABLE 2 Comp. IUPAC name Inter. No. Structure No. ¹NMR (Solvent, δ ppm)2 2,2-Dimethyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester  

2 (CD₃OD): 1.19 (s, 9H), 1.54 (d, J = 7.03 Hz, 3H), 2.33 (s, 3H), 4.42(q, J = 7.03 Hz, 1H), 5.13 (s, 2H), 6.70 (s, 1H), 7.07-7.10 (m, 2H),7.12-7.15 (m, 1H), 7.55 (s, 1H). 3 Acetic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2- methyl-benzyl ester  

3 (CD₃OD): 1.54 (d, J = 7.03 Hz, 3H), 2.04 (s, 3H), 2.33 (s, 3H), 4.42(q, J = 7.03 Hz, 1H), 5.13 (s, 2H), 6.70 (s, 1H), 7.07-7.10 (m, 2H),7.12-7.15 (m, 1H), 7.55 (s, 1H). 4 Benzoic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2- methyl-benzyl Ester  

4 (CD₃OD): 1.54 (d, J = 7.03 Hz, 3H), 2.31 (s, 3H), 4.42 (q, J = 7.03Hz, 1H), 5.13 (s, 2H), 6.70 (s, 1H), 7.07-7.15 (m, 2H), 7.25-7.28 (m,1H), 7.54-7.47 (m, 2H), 7.55-7.60 (m, 2H), 8.0 (d, J = 7.33 Hz, 2H). 53-Methyl-butyric acid 3-[(S)- 1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl Ester  

5 (CD₃OD): 0.93 (d, J = 7.03 Hz, 6H), 1.54 (d, J = 7.03 Hz, 3H), 2.07(hept, J = 7.03 Hz, 1H), 2.21 (d, J = 7.03 Hz, 2H), 2.33 (s, 3H), 4.42(q, J = 7.03 Hz, 1H), 5.15 (s, 2H), 6.70 (s, 1H), 7.07-7.10 (m, 2H),7.12-7.15 (m, 1H), 7.55 (s, 1H). 6 3-Phenyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)- ethyl]-2-methyl-benzyl Ester  

6 (CD₃OD): 1.54 (d, J = 7.03 Hz, 3H), 2.23 (s, 3H), 2.65 (t, J = 7.61Hz, 2H), 2.91 (t, J = 7.61 Hz, 2H), 4.40 (q, J = 7.03 Hz, 1H), 5.13 (s,2H), 6.70 (s, 1H), 7.08-7.24 (m, 8H), 7.55 (s, 1H).

Example 3 Intermediate 7 2-tert-Butoxycarbonylamino-3-methyl-butyricacid 3-{(S)-1-[1-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzylester

To a solution of(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0mmol) in DMF (2 ml) and THF (12 ml) were added EDCI (671 mg, 3.5 mmol),DMAP (427 mg, 3.5 mmol) and Boc-L-Valine (651 mg, 3.0 mmol). The mixturewas stirred at RT for 16 h, quenched with H₂O and extracted with ethylacetate. The combined organic layers were washed with H₂O, brine, anddried over Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by a column chromatography (30% ethyl acetate in hexanes)to yield Intermediate 7 as white solid.

¹H-NMR (CD₃OD; δ ppm): 0.85-1.01 (m, 12H), 1.20-1.48 (m, 18H), 1.56 (d,J=7.03 Hz, 3H), 2.01-2.20 (m, 2H), 2.35 (s, 3H), 4.03 (m, 1H), 4.42 (q,J=7.03 Hz, 1H), 4.60-4.65 (m, 1H), 5.15-5.29 (m, 2H), 7.10-7.20 (m, 2H),7.20-7.25 (m, 1H), 7.33 (s, 1H), 8.44 (s, 1H).

Example 4 Intermediate 8 2-tert-Butoxycarbonylamino-3-methyl-butyricacid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from Intermediate 7 (600 mg, 0.98 mmol)in 30 ml of MeOH according to the procedure described in Example 2.

¹H-NMR (CD₃OD; δ ppm): 0.85-0.95 (m, 6H), 1.42 (m, 9H), 1.54 (d, J=7.03Hz, 3H), 2.05 (m, 1H), 2.33 (s, 3H), 4.00 (d, J=6.15 Hz, 1H), 4.40 (q,J=7.03 Hz, 1H), 5.15-5.28 (m, 2H), 6.67 (s, 1H), 7.10-7.20 (m, 2H),7.20-7.25 (m, 1H), 7.55 (s, 1H).

Example 5 Compound 7 2-Amino-3-methyl-butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

To Intermediate 8 (390 mg, 0.94 mmol) was added 4N HCl in dioxane (8ml). The resulting solution was stirred at RT for 4 hrs, then quenchedwith H₂O, neutralized with aqueous saturated NaHCO₃ and extracted with25% isopropyl alcohol in chloroform. The combined organic layers weredried over Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by a column chromatography (5% 7N NH₃/MeOH in DCM) to yieldCompound 7 as white solid.

¹H-NMR (CD₃OD; δ ppm): 0.85 (d, J=6.74 Hz, 3H), 0.91 (d, J=6.74 Hz, 3H),1.54 (d, J=7.03 Hz, 3H), 1.96 (hept, J=6.74 Hz, 1H), 2.33 (s, 3H), 3.28(d, J=6.74 Hz, 2H), 4.42 (q, J=7.03 Hz, 1H), 5.20-5.25 (m, 2H), 6.67 (s,1H), 7.10-7.12 (m, 2H), 7.13-7.20 (m, 1H), 7.55 (s, 1H).

Example 6 Intermediate 92-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyricacid3-{(S)-1-[1-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzylester

The title compound was prepared from Compound 7 (490 mg, 1.55 mmol),Boc-L-Valine (1.01 g, 4.67 mmol), EDCI (1.04 g, 5.42 mmol) and DMAP (671mg, 5.5 mmol) according to the procedure described in Example 3.

¹H-NMR (CD₃OD; δ ppm): 0.85-0.92 (m, 12H), 1.43 (s, 9H), 1.55 (d, J=7.03Hz, 3H), 1.97 (m, 1H), 2.14 (hept, J=6.60 Hz, 1H), 2.35 (s, 3H), 3.88(d, J=7.30 Hz, 1H), 4.35 (d, J=6.90 Hz, 1H), 4.42 (, d, J=7.03 Hz, 1H),5.18-5.25 (m, 2H), 6.67 (s, 1H), 7.10-7.15 (m, 2H), 7/17-7.20 (m, 1H),7.55 (s, 1H).

Example 7 Intermediate 102-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyricacid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from Intermediate 9 (750 mg, 1.05 mmol)in 30 ml of MeOH according to the procedure described in Example 2.

¹H-NMR (CD₃OD; δ ppm): 0.89 (d, d, J=7.03 Hz, 6H), 1.44 (s, 9H), 1.54(d, J=7.33 Hz, 3H), 2.14 (hept, J=6.74 Hz, 1H), 2.33 (s, 3H), 3.74 (s,2H), 4.35-4.55 (m, 2H), 5.20 (s, 2H), 6.67 (s, 1H), 7.10-7.17 (m, 2H),7.19-7.23 (m, 1H), 7.56 (s, 1H).

Example 8 Compound 8 2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyricacid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from Intermediate 10 (450 mg, 0.87 mmol)in 8 ml of 4N HCl/Dioxane according to the procedure described inExample 5.

¹H-NMR (CD₃OD; δ ppm): 0.85 (d, J=7.03 Hz, 3H), 0.91 (d, J=6.74 Hz, 3H),0.92 (d, J=7.3 Hz, 3H), 1.14 (d, J=6.2 Hz, 3H), 1.54 (d, J=7.03 Hz, 3H),1.94 (hept, J=5.2 Hz, 1H), 2.14 (hept, J=6.2 Hz, 1H), 2.33 (s, 3H), 3.18(d, J=5.2 Hz, 1H), 4.34 (d, J=6.2 Hz, 1H), 4.42 (q, J=7.03 Hz, 1H),5.21-5.26 (m, 2H), 6.67 (s, 1H), 7.10-7.15 (m, 2H), 7.18-7.20 (m, 1H),7.55 (s, 1H).

Example 9 Intermediate 112-(2-tert-Butoxycarbonylamino-acetylamino)-3-methyl-butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from Compound 8 (405 mg, 1.28 mmol),Boc-Glycine (675 mg, 3.86 mmol), EDCI (859 mg, 4.48 mmol) and DMAP (547mg, 4.48 mmol) according to the procedure described in Example 3. Thetitle compound was purified by column chromatography using 5% 7NNH₃/MeOH in DCM.

¹H-NMR (CD₃OD; δ ppm): 0.89 (d, J=6.74 Hz, 3H), 0.91 (d, J=6.74 Hz, 3H),1.55 (d, J=7.30 Hz, 3H), 2.14 (hept, J=6.74 Hz, 1H), 2.33 (s, 3H), 4.37(d, J=5.90 Hz, 1H), 4.42 (q, J=7.03 Hz, 1H), 5.20-5.25 (m, 2H), 6.67 (s,1H), 7.10-7.12 (m, 2H), 7.13-7.20 (m, 1H), 7.55 (s, 1H).

Example 10 Compound 9 2-(2-Amino-acetylamino)-3-methyl-butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from Intermediate 11 (320 mg, 0.68 mmol)with 10 ml of 4N HCl/Dioxane according the procedure described inExample 5.

¹H-NMR (CD₃OD; δ ppm): 0.89 (d, J=6.74 Hz, 3H), 0.91 (d, J=6.74 Hz, 3H),2.14 (hept, J=6.74 Hz, 1H), 2.33 (s, 3H), 4.37 (d, J=5.90 Hz, 1H), 4.42(q, J=7.03 Hz, 1H), 5.20-5.25 (m, 2H), 6.67 (s, 1H), 7.10-7.12 (m, 2H),7.13-7.20 (m, 1H), 7.55 (s, 1H).

Example 11 Intermediate 12 2-tert-Butoxycarbonylamino-3-phenyl-propionicacid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg, 1.0mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCI (671 mg, 3.5 mmol)and DMAP (427 mg, 3.5 mmol) according to the procedure described inExample 3. Intermediate 12 was purified by a column chromatography using35-100% ethyl acetate in hexane.

¹H-NMR (CD₃OD; δ ppm): 1.36 (s, 9H), 1.55 (d, J=7.03 Hz, 3H), 2.28 (s,3H), 2.85-2.95 (m, 1H), 3.05-3.11 (m, 1H), 4.38 (m, 1H), 4.40 (q, J=7.03Hz, 1H), 5.17 (s, 2H), 6.69 (s, 1H), 7.08-7.24 (m, 8H), 7.55 (s, 1H).

Example 12 Compound 10 2-Amino-3-phenyl-propionic acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester

The title compound was prepared from Intermediate 12 (240 mg, 0.52 mmol)with 8 ml of 4N HCl/Dioxane according to the procedure described inExample 5.

¹H-NMR (CD₃OD; δ ppm): 1.54 (d, J=7.03 Hz, 3H), 2.26 (s, 3H), 2.90-3.00(m, 2H), 3.73 (t, J=6.40 Hz, 1H), 4.40 (q, J=7.03 Hz, 1H), 5.13-5.18 (m,2H), 6.68 (s, 1H), 7.08-7.12 (m, 5H), 7.13-7.22 (m, 3H), 7.55 (s, 1H).

The following assay was used to demonstrate the potency and selectivityof the compounds according to the invention.

Example 13

The experimental animals used, were Normotensive male Dutch-Beltedrabbits (Myrtle's Rabbitry) over 6 months in age (n=4/compound/dosescreened). A single drop (50 μl) of the drug formulation, which yields0.15% or 0.3% of the active metabolite when completely hydrolyzed in 1%polysorbate 80 at pH 5.5, was administered topically by pipette onto theright eye (treated eye) at approximately 0700 hours. IOP of the rabbits(treated and untreated eyes) was measured 0 hours before and at 0.5, 1,2, 3, 4, 6 and 8 hours after topical eyedrop administration. IOP at thetime of eye drop administration (0 hours) was used as a baseline value.Prior to the tonometric measurements, 0.05% proparacaine (50 μl) wasadministered to each eye. Tonometric IOP measurements were obtained witha Mentor Pneumontonmeter. Additionally, all studies were masked. Atleast 1 week of wash-out time was allowed for each rabbit betweendosings. All animals were examined for sedation, ocular irritation, andchanges in pupil diameter throughout the course of the experiments.

The data collected from the compounds of the present invention, IOPexperiments, showed that the pro-drug iso-Butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester has an IOPlowering capacity at the tested concentration that has equal orcomparable efficacy to Alphagan P® and has longer intraocular pressureduration than Alphagan P® (FIG. 1).

Example 14

This example shows the intraocular pressure-lowering effect ofiso-Butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzylester containing composition as compared to placebo. The intraocularpressure of the monkeys treated with the iso-Butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester containingcomposition, maintain the decrease in intraocular pressure for up to 24hours.

What is claimed is:
 1. A pharmaceutical composition for loweringintraocular pressure, administered topically to the eye of a subject inneed of such treatment, comprising a compound having a structure ofFormula II

wherein: R¹ is H or optionally substituted C₁₋₃ alkyl; R² is H oroptionally substituted C₁₋₃ alkyl; R³ is H, optionally substituted C₁₋₁₀alkyl, optionally substituted heterocycle or optionally substitutedaryl; and R is optionally substituted C₁₋₁₀ alkyl, optionallysubstituted heterocycle or optionally substituted aryl; or apharmaceutically acceptable salt thereof; and pharmaceuticallyacceptable carriers, preservatives, co-solvents, buffering agents,viscosity building agents, purified water.
 2. The pharmaceuticalcomposition according to claim 1, wherein the compound having astructure of Formula II is selected from: iso-Butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;2,2-Dimethyl-propionic acid3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester; Acetic acid3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester; Benzoic acid3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;3-Methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzylester; 3-Phenyl-propionic acid3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;2-Amino-3-methyl-butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;2-(2-Amino-acetylamino)-3-methyl-butyric acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; and2-Amino-3-phenyl-propionic acid3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester.
 3. Thepharmaceutical composition according to claim 1, wherein the bufferingagents include: sodium chloride, potassium chloride, calcium chloridedihydrate, magnesium chloride hexahydrate, boric acid and sodium boratedecahydrate.
 4. The pharmaceutical composition according to claim 1,wherein the viscosity building agents include: polyvinyl alcohol,polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropylcellulose.
 5. The pharmaceutical composition according to claim 1,wherein the co-solvents include: polysorbate 20, polysorbate 60,polysorbate 80, Pluronic F-84, Pluronic F-68, Pluronic P-103,cyclodextrin, Solutol.
 6. The pharmaceutical composition according toclaim 1, wherein the preservatives include: stabilized oxychlorocomplex, stabilized chlorine dioxide, benzalkonium chloride, thimerosal,chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,edetate disodium, sorbic acid, Onamer M.
 7. The pharmaceuticalcomposition according to claim 1, further formulated as a solution inwater at a pH of 5.5 to 8.0.
 8. The pharmaceutical composition accordingto claim 1, wherein the compound having a structure of Formula II iscomprised from 0.01 to 5 percent.
 9. The pharmaceutical compositionaccording to claim 6, wherein the preservative will range from 0.001% to1%.
 10. The pharmaceutical composition according to claim 5, wherein theco-solvents are employed at a level of from 0.01% to 2% by weight. 11.The pharmaceutical composition according to claim 4, wherein theviscosity building agents are employed at a level of from 0.01% to 2% byweight.
 12. A pharmaceutical composition for lowering intraocularpressure comprising 0.01 to 5 percent of a compound having a structureof Formula II

wherein: R¹ is H or optionally substituted C₁₋₃ alkyl; R² is H oroptionally substituted C₁₋₃ alkyl; R³ is H, optionally substituted C₁₋₁₀alkyl, optionally substituted heterocycle or optionally substitutedaryl; and R is optionally substituted C₁₋₁₀ alkyl, optionallysubstituted heterocycle or optionally substituted aryl; or apharmaceutically acceptable salt thereof; and a pH of 5.5 to 8.0 and atleast one co-solvent from 0.01% to 2% by weight, and at least oneviscosity building agent from 0.01% to 2% by weight and at least onepreservative from 0.001% to 1%, wherein said pharmaceutical compositionis an aqueous liquid formulated as an eye drop suitable for topicaladministration.